Heterocyclic thioamides of 4-substituted syringic acid and their preparation

ABSTRACT

Heterocyclic thioamides of 4-substituted syringic acid, and methods of their preparation, are described. The compounds have prolonged ataraxic or tranquilizing action upon the central nervous system.

United States Patent Pifferi Jan. 21, 1975 HETEROCYCLIC THIOAMIDES OF 4-SUBSTITUTED SYRINGIC ACID AND [56] References Cited THEIR PREPARATION UNITED STATES PATENTS [75] Inventor: Giorgio Piiieri, Milan, Italy 3,432,549 3/1969 Kasitreiner 260/559 R 731 Assignee: I.S.F.S.P.A., Milan, Italy OTHER PUBLICATIONS Reid, Organic Chemistry of Bivalent Sulfur, Vol. IV, [22] 1973 Chemical Publishing Co., New York, 1962, pp. 50 & [2i] Appl. No.: 328,693 48.

Wagner et 211., Synthetic Organic Chemistry, John Related US. Application Data Wl&S,NYk,l9,.7. [62] Division of Ser. No. 93,460, Nov. 27, 1970, Pat. No. l ey ons ew or 53 p 82 3355317 Primary Examiner-Richard J. Gallagher [30] Foreign Application Priority Data Attorney, Agent, or Firm-Flynn & Frishauf July 3i, i970 Italy 28164/70 57 ABSTRACT Heterocyclic thioamides of 4-substituted syringic acid, [52] 260/243 260/244 g gagg ig. and methods of their Preparation, are described. The [51] Int Cl and 93/10, (307d 91/16 COM 85/08 compounds have prolonged ataraxic 0r tranquilizing [58] Field of Search 260/3067 R, 307 F, 243 B, the central arms 5 Claims, N0 Drawings 1 2 HETEROCYCLIC THIOAMIDES ()F being endowed with a prolonged ataraxic or tranquiliz- 4-SUBSTITUTED SYRINGIC ACID AND THEIR ing action upon the central nervous system without PREPARATION compromising the reflexes and the motorial coordination. Furthermore they show a very low toxicity, a fa- RELATED APPLK ATION 5 vorable therapeutic coefficient, and the absence of col- This application is a division of application Ser. No. lateral effects on the circle. 93.4 60v filed Nov. 27, 1970, now US. Pat. No. The new thioamides of the invention are character- 3,755,3l7. ized with respect to the corresponding amides in that The present invention concerns new thioamides of they have a more prolonged effect. Although not wish- 4-substituted syringic acid having activity on the cen- [(1 ing to bound the present invention to any theory, it can tral nervous system and the methods for their preparabe supposed that this prolonged effect is to be put in retion. According to one ofits aspects the invention comlation with the greater resistance to hydrolysis which prises, more in particular, the derivatives of the forthe thioamidic bond presents compared with the mula: amidic bond.

(II-I 0 The new compounds of the present invention can be S prepared prcvailingly according to one ofthe following A synthesis methods: x I. An excess of a suitable 4-substituted syringic alde- V hyde is warm reacted with sulphur and a secondary CH O heterocyclic based in the Willgeroth reaction con- 3 ditions according to the following scheme:

i s OCH s p n A B0 CHO S H X 2 V 1 V OCH OCH 3 wherein R=CH;,-,C H ,CH -,CO- or C H OCO, 2. A second synthesis method consists in treating and suitable tertiary amides of 4-substituted syringic X acid with an excess of phosphorus pentasulphide V according to the following scheme:

OCH OCH 3 3 0 P s g n A R0 C-N x 5 RO- .c-px

V V g OCH t 3 represents the residue ofa saturated secondary heteroi The sulphuration reaction is effected in an organic cyclic base having 4, 5, 6 or 7 atoms in the ring, solvent, such as pyridine, atatemperature of from 70 wherein X represents CH S- or C to 150C, preferably by heating to 100C and main- NH-. Examples of heterocyclic bases from which m ning at this temperature for some hours.

3. A third variant considers the condensation of the the thiobenzoic acid chloride, suitably substituted in A the positions 3,4,5, with an excess of a secondary ..N X heterocyclic base according to the following scheme:

CH O

n c c1 HN X 5 RO- c-u x HCl groups preferred in the thioamides of present invention The invention will now be illustrated in detail as to its may be derived are: pyrrolidine. l,3-thiazolidine, preparative aspect by the following examples which imidazolidine. l,2-oxazolidine. l,3-oxazolidine, piperishould not be considered as having any limitative chardine piperazine, tetra-hydro-l,Z-oxazine, tetra-hydroacter. 1.3-oxa2ine. tetra-hydro-l, l 4-oxazine, (morpholine),

EXAMPLE 1 ICITll'lLVLlIO' l 4-thiazane, perhydroazepine.

According to another aspect of the invention the ,5trimethoxythiobenzoyll'tetrahydro-l,4- herein described new thiamides can be used in therapy OXflZifle A mixture of 3g. 3.4.5-trimethoxyhenzaldehyde. 0.53 g. of precipitated sulphur and 0.95 g. of morpholine was heated at 140C for 75 minutes. It was then cooled to room temperature and the residue was crystallized from ethanol giving a very good yield of the desired product, m.p. 138-l40C. Infrared spectrum (Nujol): 1,580 and 1,500 (benzenic ring stretching), 1,110 (tetrahydro-l,4-oxazine) and 850 cm (aromatic y CH).

Analysis:

Calculated for H Nos c 56.55; H 6.44; N 4.71; 10.78

FUUnLlI c 56.42; H 6.70; N 4.84; 5 11.10

EXAMPLE 2 4-(3,4,5trimethoxythiobenzoyl)-tetrahydro-1,4- thiazane A mixture of 4.1 g. 3,4,5-trimethoxybenzaldehyde, 0.72 g. precipitated sulphur and 1.57 g. tetrahydro-1,4- thiazane was heated to 140C and kept at this temperature for 1 /2 hours. The raw residue was then treated as in example 1, giving a very good yield of the desired product, m.p. 163-l65C. Infrared spectrum (Nujol): 1,580 and 1,490 (benzenic ring stretching), 1,125 (CO) and 845 cm (aromatic CH).

Analysis:

Calculated for C H JN'O S C 53.63. H 6.11, N 4.47; S 20.45

Found: C 53.26; H 6 N 4.36; S 20.90

EXAMPLE 3 3-( 3.4,5-trimcthoxythiobcnzoyl )-1 .3-thiazolidine A mixture of 5g. 3-(3,4,5-trimethoxybenzoyl)-l.3- thiazolidine and 4 g. phosphorus pentasulphide in 50 ml. anhydrous pyridine was heated under stirring to 100C and kept at this temperature for 6 hours. 1t was then cooled, poured into diluted hydrochloric acid solution, extracted with chloroform, and the organic extracts were washed with a diluted sodium carbonate solution and then with water. After drying on sodium sulfate the solvent was distilled off and the residue was crystallized from isopropyl ether-ethanol 95:5. The desired product was obtained in a very good yield, m.p. 132134C. Infrared spectrum (Nujol): 1,590 and 1,500 (benzenic ring stretching), 1,125 (CO ether) and 832 (aromatic y CH).

Analysis:

Calculated for (",,,H.,No,s. 52.17; H 5.72; N 46s; 5 21.40

' 11111611; 52.33. H 5.77; N 4.60; s 2123 EXAM PLE 4 2-(3,4.5-trin1ethoxythiobenzoyl)-1,Z-oxazolidine A mixture of 17 g. 2-(3,4,5-trimethoxybenzoyl)-l,2- oxazolidine, and 14 g. phosphorus pentasulphide in 150 m1. anhydrous pyridine was heated to 100C and kept under stirring at this temperature for 5 hours. It was cooled, poured into a diluted solution of hydrochloric acid and extracted three times with chloroform. The

organic extracts were gathered and washed with a diluted solution of sodium carbonate. then with water and finally dried on sodium sulphate. The solvent was distilled off and the residue was subjected twice to chromatography on a disactivated silicagel column by eluting with chloroform-methanol :5. The unitary central fractions. after control on a plate (Rf 0.46) were extracted with methanol and the solvent was evaporated. The residue was crystallized twice form methanol to give a good yield of the desired product, m.p. 105107C. lnfrared spectrum (Nujol): 1,590 and 1,500 (benzenic ring stretching), 1,120 (CO ether-- and 850 cm' (aromatic CH).

Analysis:

Calculated for c,,H,,No,s: c 55.10. H 6.05; N 4.94; 5 11.31

Found: c' 54.85; H 6.04; N 4.97; 5 11.66

EXAMPLE 5 4-(4-acetoxy-3,S-dimethoxythiobenzoyl)-tetrahydro- 1,4-thiazane A mixture of 1 g. 4'-( 4-acetoxy-3,5- dimethoxybenzoyl)-tetrahydro-l,4-thiazane, 0.82 g. phosphorus pentasulphide and 10 ml. anhydrous pyridine was heated under stirring to C and kept at this temperature for 5 hours, then cooled and poured into an excess of 107: hydrochloric acid. The mixture was repeatedly extracted with chloroform. the gathered extracts were washed with a diluted solution of Na CO,,, then with water and then they were dried on sodium sulfate. The solvent was distilled off and the residue was crystallized from ethanol and ethyl acetate. The desired product was obtained in good yields, m.p. 222-224C. infrared spectrum (Nujol): 1,760 (C O ester). 1,600 and 1.500 (benzenic ring stretching). 1135 (CO) and 850 cm (aromatic y CH). Analysis:

Calculated for Found: C 52.50; H 5.70; N 4.00. S 19.01

The following tests were employed for the evaluation of the neuropsychic activity of the compounds of the invention on the animal: behavior screening in the mouse according to lrwin (Gordon Res. Conf. Med. Chem. New London, N.H. 1959), spontaneous motility in the mouse (Dunham and Mija Am. Pharm. Assoc; Sci. Ed.'46, 208, 1957), motorial coordination in the mouse, conditioned reflexes in the rat according to the Cook and Wcidley method (Annals N.Y. Accad. Sci. 66, 740, 1957) modified by Mafii (j. Pharm. Pharmac., 11, 129, 1959). These methods are briefly described in the following.

The behavior screening in the mouse consists in the systematic observation of groups ofthree mice per dose treated with standardized doses (10 30 60 100 300 1,000 mg/kg i.p.) of the test pharmaceuticals. The psychosedative, neurosedative, neurovegetative, miorelaxing activities and the acute toxicity were observed and evaluated.

The spontaneous motility in the mouse was evaluated by using groups of five mice treated with various doses, which mice were put in a cage having a floor made of steel bars through which very low voltage current was passed. ln moving. the animals caused the closure of circuits with the paws and said movements were quantized. surveyed and registered by a special printing apparatus.

The motorial coordination was evaluated with the rota rod test, which consists in putting mice treated with various doses on a rod of rough plastic material rotating at a speed 12 revolutions per minute. The controls remain on the rod for more than 3 minutes: the activity of the product on the motorial coordination was evaluated considering the time of permanence on the rod.

The action on the conditioned reflexes was evaluated by utilizing the pole climbing avoidance test": the apparatus is comprised by a soundproof box, the floor of which consists of metal bars connected to an electric stimulator. Moreover, the box contains a clock and a wooden stake, which is attached to the centre of the cover and comes down to 2 cm. from the floor. The stake represents the security area on which the rats may shelter to escape an electric shock. The experimental scheme to which the rats were subjected after introduction into the box was the following: seconds of silence, 15 seconds of acustic stimulus. seconds of associated acustic and electrical stimulus. The response of the animal interrupts this scheme. The animal's mounting on the stake during the period of silence was called CR (secondary conditioned response), the mounting during the aeustic stimulus was called CR, (primary conditioned response). and the mounting during the electric stimulation was call UR (unconditioned response). The CR was interpreted as anxious response and for this evaluation the test was in the rat. whereas the psychosedative and neurosedative activities are less important. The neurovegetative activity in the mouse is non-existent. Again in the mouse, the products show a scare miorelaxing activity and do little to influence the spontaneous activity and the motorial coordination. The described properties together with a low toxicity and a non-significant pressor activity (determined by measuring the arterial pres- ,sure in the anaesthesized cat), allow that these compounds psychoactive character. The administration of the be defined as drugs having selectiveproducts can be effected orally or parenterally, and said products can be administered alone or in association with suitable pharmaceutical solid or liquid supports.

A very important fact which was evidenced by the 'tests made on the animals to evaluate the neuropsychic activity of the compounds of the present invention.

wherein R represents CH;,-. C- H CH;,CO. or C- ,H,,OCO. and

applied. A

Some representative results are reported in the fol- X lowing Table. V

TABLE Com- Psycho- Neuro- Neuro- Miore- DL Arterial Spon- Rota Anxious pound of the sedative sedative vegetative laxing mouse pressor taneous rod response Example activity activity activity activity mg/kg activity motility ED, ED mg/kg ED Ep mg/kg ED mg/kg ED i.p. ED ED mg/kg {fig/kg i.p. i.p. mg/kg mg/kg mg/kg i.p. i.p. e.v. 0s 0s 0s i.p.

1 I00 300 1000 300 1000 30 165 200 30 2O 3 250 400 1000 500 IO0O 30 600 600 25 4 200 500 400 300 700 30 220 220 35 I5 From the examination of the data of the preceding Table it can be observed that the most important activis selected from the group consisting of ity oi the tested products is the antianxious activity ob- E z served by means of the pole climbing avoidance test" I l H2C'CH2 H2C CH2 OCH H C CH N- s N- v H2C" CH2 CH2 CH2 cn CH CH --Ci l N H C CH CH "CH 4. Compound of claim com prising trimethoxythiobenzoyl l ,Z-oxuzolidinc.

5. Compound of claim I comprising 4-(4 ucctoxy- 3 ,S-dimethoxythiohcnz oyl) -thiumorpho|inc.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT N0. 3,862,138

DATED January 21, 1975 D INVENTOR(S) y GIORGIO PIFFERI it is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

PColumn 4, line 9: replace "form with from Column 6, line 4: replace "scare" with scarce Column 6, line 60 et seq.: delete the following:

CH CH CH CH l 2 2 N H2C 2 2 N CH CH CH2 CH2 Columns 7 and 8, lines 1 through 14: delete the underscoring of the formulae.

Columns 7 and 8, lines 1 through 14: delete the following:

HC-CH-CH i 2 2 N- HC-CH-CH Commissioner ofPaIenIs and Trademarks Signed and Scalcdthis twenty-fifth Day OF November 1975 tsiAL] Arrest:

RUTH C. MASON c. MARSHALL DANN Arresting Officer 

2. Compound of claim 1 comprising 4-(3,4,5-trimethoxythiobenzoyl)-thiamorphaline.
 3. Compound of claim 1 comprising 3-(3,4,5-trimethoxythiobenzoyl)-1,3-thiazolidine.
 4. Compound of claim 1 comprising 2-(3,4,5-trimethoxythiobenzoyl)-1,2-oxazolidine.
 5. Compound of claim 1 comprising 4-(4 acetoxy-3,5-dimethoxythiobenzoyl)-thiamorpholine. 